Method of predicting a predisposition to qt prolongation

ABSTRACT

The present invention describes an association between genetic polymorphisms in the ABCC2 gene and a predisposition to prolongation of the QT interval, and provides related methods for the prediction of such a predisposition, the administration of QT interval-prolonging compounds to individuals having such a predisposition, and determining whether a compound is capable of inducing QT prolongation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of co-pending U.S. ProvisionalPatent Application No. 61/167,139, filed 6 Apr. 2009, which is herebyincorporated herein.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates generally to a method of predicting anindividual's predisposition to QT prolongation, and more particularly,to a method of predicting such predisposition based on a sequence of theindividual's ABCC2 (ATP-binding cassette, sub-family C, member 2) gene.

2. Background

Prolongation of the electrocardiographic QT interval (the time betweenthe start of the Q wave and the end of the T wave) is referred to aslong QT syndrome (LQTS). LQTS may comprise a genetic component. In somepatients with LQTS, QT prolongation can be a chronic condition. In somepersons, LQTS may be induced by the administration of an activepharmaceutical ingredient that prolongs the QT interval. A number ofcompounds are believed to be capable of prolonging the QT interval.These include amiodarone, arsenic trioxide, bepridil, chloroquine,chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide,domperidone, droperidol, erythromycin, halofantrine, haloperidol,ibutilide, iloperidone, levomethadyl, mesoridazine, methadone,pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin,and thioridazine.

Other compounds are suspected of being capable of prolonging the QTinterval, although such prolongation has not been definitivelyestablished. These include alfuzosin, amantadine, azithromycin, chloralhydrate, clozapine, dolasetron, felbamate, flecainide, foscarnet,fosphenytoin, gatifloxacin, gemifloxacin, granisetron, indapamide,isradipine, levofloxacin, lithium, moexipril, moxifloxacin, nicardipine,octreotide, ofloxacin, ondansetron, quetiapine, ranolazine, risperidone,roxithromycin, tacrolimus, tamoxifen, telithromycin, tizanidine,vardenafil, venlafaxine, voriconazole, and ziprasidone.

Individuals at risk of suffering LQTS are advised not to use still othercompounds, due to the possibility that they may prolong the QT interval.These include albuterol, amitriptyline, amoxapine, amphetamine,dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram,clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine,dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole,fluoxetine, galantamine, imipramine, isoproterenol, itraconazole,ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine,midodrine, norepinephrine, nortriptyline, paroxetine, phentermine,phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine,ritodrine, salmeterol, sertraline, sibutramine, solifenacin,terbutaline, tolterodine, trimethoprim-sulfa, and trimipramine.

By fluorescence in situ hybridization (FISH), Taniguchi et al. and vanKuijck et al. mapped the human MRP2/CMOAT gene to 10q24. Taniguchi etal., A human canalicular multispecific organic anion transporter (cMOAT)gene is overexpressed in cisplatin-resistant human cancer cell lineswith decreased drug accumulation, Cancer Res. 56: 4124-4129, 1996.PubMed ID: 8797578; van Kuijck et al., Assignment of the canalicularmultispecific organic anion transporter gene (CMOAT) to human chromosome10q24 and mouse chromosome 19D2 by fluorescent in situ hybridization,Cytogenet. Cell Genet. 77: 285-287, 1997. PubMed ID: 9284939. Toh et al.determined the exon/intron structure of the human MRP2/CMOAT gene. Theyfound that the human gene contains 32 exons and spans 200 kb or moregenomic DNA. Toh et al., Genomic structure of the canalicularmultispecific organic anion-transporter gene (MRP2/cMOAT) and mutationsin the ATP-binding-cassette region in Dubin-Johnson syndrome, Am. J.Hum. Genet. 64: 739-746, 1999. PubMed ID: 10053008.

Evers et al., who referred to cMOAT as multidrug resistance-associatedprotein-2 (MRP2), studied its drug export activity in polarized kidneyin MDCK cells. In contrast to MRP1, cMOAT was found predominantlyintracellularly in nonpolarized cells, suggesting the cMOAT requires apolarized cell for plasma membrane routing. They found that when kidneyepithelial MDCK cells were grown in a monolayer, cMOAT localized to theapical plasma membrane. Their studies demonstrated that cMOAT causestransport of organic anions, including a substrate not shown to betransported by organic anion transporters previously. Transport wasinhibited only inefficiently by compounds known to block MRP1. They alsoshowed that cMOAT caused transport of the anticancer drug vinblastine tothe apical side of a cell monolayer. They concluded that cMOAT is a5-prime-adenosine triphosphate binding cassette transporter that may beinvolved in drug resistance in mammalian cells. Evers et al., Drugexport activity of the human canalicular multispecific organic aniontransporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA,J. Clin. Invest. 101: 1310-1319, 1998. PubMed ID: 9525973.

SUMMARY OF THE INVENTION

The present invention describes an association between geneticpolymorphisms in the ABCC2 gene and a predisposition to prolongation ofthe QT interval, and provides related methods for the diagnosis of suchpredisposition and for the administration of QT interval-prolongingcompounds to individuals having such a predisposition.

A first aspect of the invention provides a method of administering to anindividual a compound capable of prolonging the individual's QTinterval, the method comprising determining at least a portion of anindividual's ABCC2 gene sequence; and in the case that a portion of theindividual's ABCC2 sequence is associated with an increased risk of QTprolongation, administering to the individual a quantity of the compoundless than would be administered to an individual having a ABCC2 genesequence not associated with an increased risk of QT prolongation, orelecting instead to treat the individual with a different compound notknown to be associated with QT prolongation.

A second aspect of the invention provides a method of determiningwhether or not an individual is predisposed to prolongation of the QTinterval, the method comprising: determining at least a portion of anindividual's ABCC2 gene sequence.

A third aspect of the invention provides a method of administering acompound capable of prolonging a QT interval to an individual sufferingfrom long QT syndrome (LQTS), the method comprising: determining atleast a portion of an individual's ABCC2 gene sequence; andadministering to the individual a quantity of the compound based on theindividual's ABCC2 gene sequence.

A fourth aspect of the invention provides a method of administering toan individual a compound capable of prolonging the individual's QTinterval, the method comprising: characterizing an expression product ofan individual's ABCC2 gene; and in the case that the characterizedexpression product is associated with an increased risk of QTprolongation, administering to the individual a quantity of the compoundless than would be administered to an individual having an expressionproduct not associated with an increased risk of QT prolongation.Expression products of the ABCC2 gene may include, for example, mRNA andprotein including any isoform of the mRNA and protein.

A fifth aspect of the invention provides a method of determining whetheran individual is predisposed to prolongation of the QT interval, themethod comprising: characterizing an expression product of anindividual's ABCC2 gene.

A sixth aspect of the invention provides a method of administering acompound capable of prolonging a QT interval to an individual sufferingfrom long QT syndrome (LQTS), the method comprising: characterizing anexpression product of an individual's ABCC2 gene; and administering tothe individual a quantity of the compound based on the characterizedexpression product.

A seventh aspect of the invention provides a method of determiningwhether a compound is capable of prolonging QT interval in anindividual, the method comprising: measuring an expression product ofthe individual's ABCC2 gene; administering to the individual a quantityof the compound; remeasuring the expression product of the individual'sABCC2 gene; and determining whether the compound is capable ofprolonging the individual's QT interval based on a difference in themeasurements of the expression product of the individual's ABCC2 gene.

An eighth aspect of the invention provides a method of determiningwhether a compound is capable of prolonging a QT interval in anindividual, the method comprising: measuring a QT interval of each of aplurality of test organisms, the plurality including a first testorganism having a ABCC2 genotype associated with a predisposition forprolongation of QT interval and a second organism having ABCC2 genotypenot associated with a predisposition for prolongation of QT interval;administering a quantity of the compound to each of the plurality oftest organisms; remeasuring a QT interval of at least the first testorganism; and determining that the compound is capable of prolonging aQT interval in an individual in the case that the remeasured QT intervalis greater than the measured QT interval. Test organisms may include,for example, humans, animal models, and/or cell lines.

DETAILED DESCRIPTION OF THE INVENTION

As indicated above, the invention provides a method of predicting anindividual's predisposition to QT prolongation based on the sequence ofthe individual's ABCC2 (ATP-binding cassette, sub-family C, member 2)gene.

At least one single nucleotide polymorphisms (SNPs) within the ABCC2gene has been found to have a significant correlation to apredisposition to drug-induced QT prolongation. Table 1, below, showssuch SNPs and the genotypes associated with QT prolongation followingthe administration of iloperidone.

TABLE 1 ABCC2 SNP Genotypes and QT Prolongation Following Administrationof Iloperidone Affymetrix Lowest QTc SNP No. rs_number Position change Pvalue Allele A Allele B SNP_A-2253129 rs4919395 101532953 non-BB0.009208217 C T SNP_A-2262953 rs2804398 101548624 non-BB 0.000421121 A TSNP_A-1928598 rs2273697 101553805 AB 0.479636886 C T SNP_A-1927451rs3740065 101595683 AB 0.760583618 C T SNP_A-2068049 rs7067971 101606569non-BB 4.02462E−07 A G SNP_A-4268713 rs2256700 101623437 non-BB0.595645464 A G SNP_A-2004488 rs2256678 101623769 non-BB 0.003956423 C T

A genotype of GG at the rs7067971 locus was found to most accuratelypredict a predisposition to QT prolongation. This genotype is includedamongst all genotypes associated with a predisposition to QTprolongation. Therefore, individuals having a genotype of GG at thers7067971 locus may be considered predisposed to QT prolongationfollowing the administration of a compound capable of prolonging the QTinterval.

Since the QT interval changes with changes in heart rate, the QTinterval is often measured as a corrected QT (QTc) interval. Any numberof formulas may be employed to calculate the QTc, including, forexample, the Fridericia formula (QTcF), the Bazett formula (QTcB), andthe Rautaharju formula (QTp), among others. In the studies describedherein, QT was calculated using the Fridericia formula. However, thepresent invention includes the use of any such formula or method forcalculating a QTc or an uncorrected QT.

As noted above, a large number of compounds are known or suspected to becapable of inducing QT prolongation in some individuals, includingindividuals not suffering from LQTS. One such compound is iloperidone.Iloperidone is disclosed in U.S. Pat. Nos. 5,364,866, 5,658,911, and6,140,345, each of which is incorporated herein by reference.Metabolites of iloperidone may also be capable of prolonging a QTinterval. Metabolites of Iloperidone, e.g.,1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol,are described in International Patent Application Publication No.WO03020707, which is also incorporated herein by reference.

Other iloperidone metabolites include:1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone;1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone;4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol;4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α-methylbenzenemethanol;1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone;and1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone.See U.S. Pat. No. 5,364,866 and International Patent ApplicationPublication Nos. WO9309276 and WO9511680, which are incorporated hereinby reference.

Using the genotypes at the SNP loci above, it is possible, with a highdegree of certainty, to predict an individual's predisposition to QTprolongation. Table 2 below shows the results of a study of 174individuals, each of whom was genotyped at the rs7067971 locus and theirQT interval measured following the oral administration of 24 mg/dayB.I.D. of iloperidone for a period of two weeks.

TABLE 2 QT Prolongation and Presence or Absence of a Genotype forSNP_A-2068049, rs7067971 Associated with a Predisposition to QTProlongation Change negative positive Threshold Low QT High QT Oddspredictive predictive (msec) −test +test −test +test Ratio p valuesensitivity specificity value value QT > 5 64 0 101 13 0.969 0.11 1.000.39 1.00 QT > 15 104 2 61 11 9.38 0.0044 0.15 0.98 0.63 0.85 QT > 30144 7 21 6 5.88 0.0033 0.22 0.95 0.87 0.46

As can be seen in Table 2, an individual's ABCC2 sequence at theSNP_A-2068049, rs7067971 locus is highly predictive of whether theindividual will experience QT prolongation following the administrationof iloperidone. For example, using the lowest threshold of a change inQTc interval (between baseline and the end of the second week) greaterthan 5 milliseconds (normal QTc intervals are between 0.30 and 0.44seconds for males and between 0.30 and 0.45 for females), 13 of thoseindividuals with the GG genotype (test is considered positive if thegenotype for SNP_A-2068049, rs7067971 is GG) experienced QT prolongationwhile no such individuals did not. The resulting sensitivity(probability that the individual will have a SNP genotype associatedwith a predisposition to QT prolongation, given that he/she experiencedQT prolongation) of 0.11, specificity (probability that the individualwill not have a SNP genotype associated with a predisposition to QTprolongation, given that he/she did not experience QT prolongation) of1.0, negative predictive value (probability that the individual will notexperience QT prolongation, given that he/she does not have a SNPgenotype associated with a predisposition to QT prolongation) of 0.39,and a positive predictive value (probability that the individual willexperience QT prolongation, given that he/she has a SNP genotypeassociated with a predisposition to QT prolongation) of 1.0, permit oneto predict with great accuracy that an individual possessing the GGgenotype is likely to experience QT prolongation.

The use of higher thresholds (i.e., QTs greater than 15 and 30milliseconds) yielded markedly increased negative predictive values(0.63 and 0.87, respectively). The associated decrease in positivepredictive values, from 1.0 for QTs greater than 5 milliseconds to 0.46for QTs greater than 30 milliseconds) suggests that additional factorsaffect more severe QT prolongation.

As the data in Table 2 show, an individual's ABCC2 sequence at the SNPloci above may be used to predict whether an individual is predisposedto QT prolongation due to the administration of a compound capable ofprolonging the QT interval. That is, individuals having a genotype of GGat the rs7067971 locus may reliably be predicted to experience aprolonged QT interval (i.e., a change in QT interval of at least 5milliseconds) following the administration of a compound capable ofprolonging the QT interval. Similarly, individuals having a genotypeother than GG at the rs7067971 locus may reliably be predicted to notexperience severe QT prolongation (i.e., a change in QT interval ofgreater than 15 milliseconds) following the administration of a compoundcapable of prolonging the QT interval.

The ability to make such predictions may be used in deciding whether totreat an individual with a particular compound and/or in determining thedosage appropriate for the individual. For example, an individualpredicted to experience QT prolongation may be treated with analternative compound not known or suspected to cause QT prolongation ormay be administered a lower dose of a compound capable of causing QTprolongation than would be administered to an individual not predictedto experience QT prolongation.

The present invention also includes the administration of anothercompound useful in treating LQTS, in addition to one or more of thecompounds above. Compounds useful in treating LQTS and/or preventingcardiac events resulting from LQTS, include, for example, beta blockers,such as propranolol, nadolol, atenolol, metoprolol.

The present invention also includes the prediction of an individual'spredisposition for QT prolongation based on one or more of the SNP lociabove in combination with the individual's genotype or gene sequence atone or more additional genes or loci. For example, International PatentApplication Publication No. WO2006039663, incorporated herein byreference, describes a method of treating an individual with a compoundcapable of inducing QT prolongation based on the individual's CYP2D6genotype. Other genotypes and/or gene sequences may similarly be used incombination with the SNP loci above, including those associated withLQTS. It should also be understood that the present invention includesthe characterization of an expression product of the ABCC2 gene ratherthan, or in addition to, the determination of one or more SNP genotypeswithin the ABCC2 gene. For example, by determining a sequence of an mRNAstrand transcribed from the ABCC2 gene, it is possible to determine thesequence of the ABCC2 gene itself and, as described above, determinewhether the ABCC2 gene sequence is associated with a predisposition toQT prolongation.

Similarly, by properly characterizing a functional peptide or protein,including the ABCC2 enzyme, translated from the mRNA strand above, it ispossible to determine the sequence of the ABCC2 gene itself and, asdescribed above, determine whether the ABCC2 gene sequence is associatedwith a predisposition to QT prolongation. In addition, the presentinvention includes determining whether a compound is capable ofprolonging a QT interval in an individual. This may be done, forexample, by measuring a change in QT interval in a test organism (e.g.,human, animal model, cell line) known to possess a ABCC2 genotypeassociated with a predisposition to QT prolongation following theadministration of a quantity of compound under study.

Preferably, the compound is also administered to a test organism knownto possess an ABCC2 genotype not associated with a predisposition to QTprolongation.

The foregoing description of various aspects of the invention has beenpresented for purposes of illustration and description. It is notintended to be exhaustive or to limit the invention to the precise formdisclosed, and obviously, many modifications and variations arepossible. Such modifications and variations that may be apparent to aperson skilled in the art are intended to be included within the scopeof the invention as defined by the accompanying claims.

1. A method of administering to an individual a compound capable of prolonging the individual's QT interval, the method comprising: determining at least a portion of an individual's ABCC2 gene sequence; and in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a quantity of the compound less than would be administered to an individual having a ABCC2 gene sequence not associated with an increased risk of QT prolongation.
 2. The method of claim 1, wherein determining includes determining the individual's genotype at the rs7067971 locus and a genotype associated with an increased risk of QT prolongation is GG.
 3. (canceled)
 4. The method of claim 1, further comprising: determining the individual's CYP2D6 genotype.
 5. The method of claim 1, wherein the compound is selected from a group consisting of: amiodarone, arsenic trioxide, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, iloperidone, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine; alfuzosin, amantadine, azithromycin, chloral hydrate, clozapine, dolasetron, felbamate, flecainide, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisetron, indapamide, isradipine, levofloxacin, lithium, moexipril, moxifloxacin, nicardipine, octreotide, ofloxacin, ondansetron, quetiapine, ranolazine, risperidone, roxithromycin, tacrolimus, tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, voriconazole, ziprasidone; albuterol, amitriptyline, amoxapine, amphetamine, dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram, clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine, dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole, fluoxetine, galantamine, imipramine, isoproterenol, itraconazole, ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine, midodrine, norepinephrine, nortriptyline, paroxetine, phentermine, phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine, ritodrine, salmeterol, sertraline, sibutramine, solifenacin, terbutaline, tolterodine, trimethoprim-sulfa, trimipramine, and metabolites, pharmaceutically-acceptable salts, and combinations thereof.
 6. The method of claim 5, wherein the compound has the formula:

wherein: R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid, pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl,

alkyl is lower alkyl, branched or straight and saturated or unsaturated; acyl is lower alkyl or lower alkyloxy bonded through a carbonyl; aryl is phenyl or phenyl substituted with at least one group, R₅, wherein each R₅ is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy; heteroaryl is is a five- or six-membered aryl ring having at least one heteroatom, Q₃ wherein each Q₃ is, independently, —O—, —S—, —N(H)—, or —C(H)═N— W is CH₂ or CHR, or N—R₉; R₁ is —H, lower alkyl, —OH, halo, lower alkoxy, trifluormethyl, nitro, or amino; R₂ is C₂-C₅ alkylene, alkenylene (cis or trans), or alkynylene, optionally substituted by at least one C₁-C₆ linear alkyl group, phenyl group or

where Z₁ is lower alkyl, —OH, lower alkoxy, —CF₃, —NO₂, —NH₂, or halogen; R₃ is lower alkyl or hydrogen; R₇ is hydrogen, lower alkyl, or acyl; R₈ is lower alkyl; R₉ is hydroxy, lower alkoxy, or —NHR₁₀; R₁₀ is hydrogen, lower alkyl, C₁-C₃ acyl, aryl,

X₁, X₂, and X₃ are, independently, —O—, —S—, ═N—, or —N(R₃)—, or X₁ and X₂ are not covalently bound to each other and are, independently, —OH, ═O, —R₃, or ═NR₃; lower is 1-4 carbon atoms; m is 1, 2, or 3; and n is 1 or
 2. 7. The method of claim 6, wherein: R is —C(O)CH₂OH, —CH(OH)C(O)CH₂OH, —C(O)OH, CH(OH)CH₃, or C(O)CH₃; R₁ is halo; X₁ and X₂ are different and are ═O, —OH, ═N—, or —O—; R₂ is C₂-C₄ alkylene or alkenylene; R₃ is hydrogen, methyl, or ethyl; X₃ is —O—; R is

(1A).
 8. The method of claim 7, wherein the compound of Formula 1 is 1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B:


9. The method of claim 7, wherein the compound of Formula 1 is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 1C:


10. A method of determining whether an individual is predisposed to prolongation of the QT interval, the method comprising: determining at least a portion of an individual's ABCC2 gene sequence.
 11. The method of claim 10, further comprising: in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a compound not known or suspected to cause QT prolongation.
 12. The method of claim 10, wherein determining includes determining the individual's genotype at the rs7067971 locus and a genotype associated with an increased risk of QT prolongation is GG.
 13. (canceled)
 14. The method of claim 10, further comprising: determining the individual's CYP2D6 genotype.
 15. A method of administering a compound capable of prolonging a QT interval to an individual suffering from long QT syndrome (LQTS), the method comprising: determining at least a portion of an individual's ABCC2 gene sequence; and administering to the individual a quantity of the compound based on the individual's ABCC2 gene sequence.
 16. The method of claim 15, wherein determining includes determining the individual's genotype at the rs7067971 locus and a genotype associated with an increased risk of QT prolongation is GG.
 17. (canceled)
 18. The method of claim 15, further comprising: determining the individual's CYP2D6 genotype. 19-21. (canceled)
 22. The method of claim 15, wherein the compound is 1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B:


23. The method of claim 15, wherein the compound is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 1C:

24-33. (canceled) 